The hepatitis C virus (HCV) is estimated to infect 170 million people worldwide and in many countries is the leading cause of chronic liver disease. Infection frequently leads to cirrhosis and hepatocellular carcinoma in long-term chronically infected patients. In most cases, clinical symptoms post-infection are mild or even subacute. Hence, many patients do not realize that they are infected until there is chronic liver damage 10-30 years after the initial infection. There are no vaccines or selective drugs currently available to treat HCV and the current standard therapies for HCV treatment are based on antiviral therapies that are not effective for a large number of patients, and are also poorly tolerated. The current best standard of care utilizes pegylated alpha-interferon and ribavirin. In the most common genotypes, this therapy is effective in less than 50% of cases and is associated with side effects and relapse after treatment cessation. Thus, there is a clear unmet need for effective therapies for the treatment of HCV infection.
HCV is an enveloped, positive-sense single-stranded RNA virus belonging to the Flaviviridae family. The 9.6 kb genome encodes for a single open reading frame, resulting in the translation of a single polyprotein of approximately 3,010 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. The flanking 5′ and 3′ untranslated regions of the viral RNA genome contain important cis-acting signals for the initiation of viral RNA replication and protein translation. The HCV life-cycle can be separated into the following phases: 1) attachment to the cell membrane and entry into the cytoplasm; 2) cytoplasmic release and uncoating of the viral genome; 3) IRES-mediated translation; 4) polyprotein processing by cellular and viral proteases; 5) RNA replication; 6) packaging and assembly; 7) release from the host cell. As the HCV life cycle depends on the activity of numerous viral enzymes, engineering of specific enzyme inhibitors is being pursued in a number of laboratories to block HCV replication. Current research is mainly directed towards inhibiting HCV by targeting the non-structural proteins NS3 (protease and helicase) and NS5B (polymerase). Without wishing to be bound by any particular mechanism, it is believed that the compounds of the present invention target a host cell mechanism.
Picornaviruses are responsible for a large number of human viral diseases. The genus enterovirus, cardiovirus, rhinovirus, aphtovirus and hepatovirus especially the polioviruses (Sb), coxsackieviruses (CV), human echoviruses, human enteroviruses, human rhinoviruses (HRV) and hanks viruses all belong to the picornaviridae family. The disease syndromes range from mild upper respiratory disease to fatal neurological or cardiac-based illnesses. Rhinoviruses are estimated to cause approximately one-third of all upper respiratory tract viral infections. Examples of diseases caused by picornaviridae viral infections include, but are not limited to e.g. in humans aseptic meningitis, poliomyelitis, herpangina, pleurodynia (Bornholm disease), myositis, rhabdomyolysis, diabetes type 1, summer fever, encephalitis, febrile illness and myocarditis. In animals rhinoviruses and the foot and mouth disease viruses can be caused by such infections.
Picornaviruses are non-enveloped single-stranded positive-sense RNA viruses. The viral RNA genome is packaged in a capsid consisting of 60 repeating protomeric units, each one containing a copy of the four viral proteins VP1, VP2, VP3 and VP4. The structural organization of the viral capsid of several picornaviruses e.g. human rhinovirus 14 (HRV-14), poliovirus and coxsackievirus B3 has been elucidated by crystallization and resolution of the three-dimensional structure.
Imidazopyrazines are known in the literature and have been reported to be effective treatments for various disorders (e.g. WO 2008/059373 (acid pump antagonists), WO 2008/057512 (kinase inhibitors), WO 2004/074289 (gastric secretion inhibitors)). In particular, there are several reports of imidazopyrazines having a use in oncology by inhibiting cyclin-dependent kinases (e.g. WO 2007/058942, WO 2007/056468 and WO 2004/026877).
Surprisingly, the imidazopyrazines disclosed here have little or no effect on cyclin-dependent kinases and more surprisingly are effective as antiviral agents against a number of different viruses that include but are not limited to HCV, HRV, Sb and CVB.